SABR Slashes Progression of AdvancedProstate Cancer

Neil Osterweil

March 27, 2020

Intense radiotherapy aimed at all metastases in men with prostate cancer with limited metastases (up to three) has been shown to slow progression of the disease.

Patients with oligometastatic disease who received stereotactic ablative radiotherapy (SABR) had a significant threefold decrease in disease progression at 6 months compared with patients who were randomly assigned to observation alone.

"Local control for SABR-treated lesions was excellent, and the adverse effects associated with SABR were mild and did not appear to affect quality of life," say the investigators, led by Ryan Phillips, MD, PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, Maryland.

"Although the approach is controversial, many men are interested in avoiding the unpleasant adverse effects and potential health risks of androgen deprivation therapy (ADT) for as long as is reasonable," they write.

These results come from outcomes of the Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 trial and were published online March 26 in JAMA Oncology.

An intriguing finding from the study was evidence that SABR may evoke an immune response.

"We observed enhanced differential clonotype expansion, clusters of similar expanded T-cell receptors, and a clinical benefit to greater baseline clonality seen only in participants treated with SABR," said senior author Phuoc T. Tran, MD, PhD, from the department of radiation oncology and molecular radiation sciences at Johns Hopkins.

"This the only data I'm aware of that really shows that radiation in isolation can cause a systemic immune response," Tran told Medscape Medical News.

Previous studies suggesting an immune response with radiation have been confounded by coadministration of radiation and chemotherapy, he said.

Drive the Disease to 'Near Extinction'

SABR appears to "alter the natural history of prostate oligometastatic disease by removing or greatly affecting signals that promote further development of micrometastatic disease," write the authors of accompanying editorial.

This hypothesis is consistent with the oligometastatic paradigm, which postulates that this is a transient phase that offers "a window of opportunity for cancer cure if equilibrium-phase lesions are ablated before polymetastatic escape occurs," write Carlo Greco, MD, and Zvi Fuks, MD, both from

the Champalimaud Centre for the Unknown, Lisbon, Portugal; Fuks is also affiliated with Memorial Sloan Kettering Cancer Center, New York City.

"Taken together, these observations support the hypothesis that all detectable oligometastatic lesions should be systematically ablated, if feasible, in an effort to maximize oligometastatic cancer cure," Greco and Fuks comment.

However, there is no clear consensus on what constitutes oligometastatic disease, they point out, and they warn that "a numerical-based decision to withhold lesion ablation may represent a strategic error, potentially reducing the benefit of metastasis-directed therapy (MDT) in the treatment of oligometastatic cancer."

"We speculate that, if clinically and technically feasible, there should be no restriction to MDT at first oligometastatic presentation and as sequential lesions appear, regardless of lesion numbers, because each lesion may potentially constitute a generator of evolving metastatogenic clonogens," they add.

Multiple rounds of MDT theoretically could "drive the disease to near extinction" and prevent the development of polymetastatic disease, they contend.

Study Details

For their study, Phillips and colleagues enrolled 54 men with recurrent hormone-sensitive prostate cancer with one, two, or three metastases detectable on conventional imaging who had not received ADT within 6 months of enrollment, or for a total of 3 or more years.

The patients were randomly assigned in a 2:1 ratio to receive either SABR, with dose and fractionation based on the size and location of each lesion, or to observation. The median age in each group was 68 years.

Prostate-specific membrane antigen (PSMA)-targeted PET-CT, a relatively new technique that is more accurate than conventional imaging, was performed during treatment planning and at day 180 of follow-up for patients assigned to SABR, but the investigators were blinded to the results to prevent bias in target-lesion selection.

The primary endpoint of progression at 6 months was measured by prostate-specific antigen increase, radiographic evidence, symptomatic progression, ADT initiation for any reason, or death.

This primary endpoint occurred in 7 of 36 men (19%) who were treated with SABR, compared with 11 of 18 (61%) who underwent observation (P = .005).

Median progression-free survival (PFS) was not reached in the SABR group vs. 5.8 months in the observation group, translating into a hazard ratio [HR] of 0.30 (P = .002).

Of the 36 men treated with SABR, 16 had baseline PET-avid lesions that, because of investigator blinding, were not included in the treatment fields.

Among all SABR-treated patients, the rate of progression at 6 months among men for whom all lesions were treated was 5%, compared with 38% for men with any lesions outside the treatment field (P = .03). The median PFS for patients with no untreated lesions was not reached, vs. 11.8 months for men in whom PET-avid lesions were missed (HR, 0.26, P = .006).

Oligometastatic vs Polymetastatic

In an interview with Medscape Medical News, Tran noted that using PSMA PET-CT for imaging appears to be very important for identifying those patients with numerous or disseminated (polymetastatic) lesions, compared with those patients with limited disease who are most likely to benefit from SABR. He emphasized, however, that the PSMA PET-CT findings were an exploratory endpoint that required further validation.

Another secondary, exploratory endpoint of the study was the use of a circulating tumor DNA (ctDNA) analysis by the CAPP-Seq (cancer personalized profiling by deep sequencing) method.

"We show, in a discovery fashion, that certain mutations in the circulation seem to distinguish patients who would benefit from SABR vs those who would not," he said.

The study was supported by the Nesbitt-McMaster Foundation, Ronald Rose and Joan Lazar, the Movember Foundation and Prostate Cancer Foundation, and the National Cancer Institute. Phillips reported receiving consulting fees and honoraria from RefleXion Medical outside the submitted work. Tran holds a licensed patent related to ablative radiotherapy compounds and methods (Natsar Pharmaceuticals). Several other authors reported financial disclosures. The full list can be found with the original article. Editorialists Greco and Fuks reported serving as cofounders of and owning stock in Ceramedix Holding, LLC.

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